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The peptide angiotensin-(1-7) as a novel treatment for complications induced by type 2 diabetes mellitus

THE PEPTIDE ANGIOTENSIN-(1-7) AS A NOVEL TREATMENT FOR
COMPLICATIONS INDUCED BY TYPE 2 DIABETES MELLITUS
by
Nicholas Michael Mordwinkin
A Dissertation Presented to the
FACULTY OF THE USC GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(PHARMACEUTICAL SCIENCES)
May 2012
Copyright 2012 Nicholas Michael Mordwinkin

The aim of this dissertation is to evaluate the impact of type 2 diabetes mellitus on oxidative stress and inflammation in the bone marrow and circulation, as well as investigate the relationship between these molecular alterations and long-term complications of diabetes, specifically cardiovascular disease. In addition, the role of the peptide Ang-(1-7) i as well as the receptor and second messager systems involved in reversing these molecular alterations and complications will also be determined. ❧ The research integrates multiple in vivo studies and a clinical study to provide a comprehensive picture of this disease state. Nitrite levels in the bone marrow and blood were measured using the Griess reaction. Expression and protein levels of molecular markers of oxidative stress and cytokines were determined using RT-PCR, western blot, and ELISA. Levels of oxidative stress, protein tyrosine nitration in the bone marrow, intracellular cytokine levels, and EPC counts were measured using flow cytometric methodologies. Tissue protein nitration was measured by immunohistochemistry. Murine heart function was determined in vivo using small animal echocardiography and thermodilution techniques, and histology was used to measure cardiomyocytes in stained heart sections. Culture of isolated bone marrow cells was used to determine various progenitor counts. ❧ Our in vivo and clinical data indicate that oxidative stress and systemic inflammation play a major role in both type 2 diabetes and gestational diabetes. In addition, we illustrate a potential link between these pathologies and endothelial and cardiovascular dysfunction in this disease state. Treatment of db/db mice with Ang-(1-7) for 14 days resulted in decreases in markers of oxidative stress and inflammation, increases in bone marrow-derived and circulating EPC, as well as increases in other bone marrow-derived progenitors involved in vasculogenesis and immune function. Lastly, Ang-(1-7) treatment helped to increase measures of cardiac function that were reduced in diabetic mice. ❧ While a focus on glucose control is still of the utmost importance, more attention needs to be spent on reversing the pre-existing cellular damage caused by oxidative stress and inflammation in diabetes. Ang-(1-7) may be one of multiple promising agents with the ability to work synergistically with currently FDA-approved therapies; together able to reduce plasma glucose levels, preventing further damage, and reverse oxidative stress and inflammation in type 2 diabetes. Combined, this therapeutic strategy could potentially significantly reduce the risk of some of the long-term and deadly complications of diabetes, including cardiovascular disease.

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THE PEPTIDE ANGIOTENSIN-(1-7) AS A NOVEL TREATMENT FOR
COMPLICATIONS INDUCED BY TYPE 2 DIABETES MELLITUS
by
Nicholas Michael Mordwinkin
A Dissertation Presented to the
FACULTY OF THE USC GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(PHARMACEUTICAL SCIENCES)
May 2012
Copyright 2012 Nicholas Michael Mordwinkin